Most connective tissues are composed primarily of collagen and exhibit hierarchical organization from the nanometer to the millimeter scale. Although the structure and mechanics of collagenous connective tissues have been studied for decades, a clear understanding of the relationships between hierarchical organization and material behavior is severely lacking. This can be attributed in large part to an inability to integrate and couple mechanics between the nanoscale, microscale and mesoscale. In theory, this integration can be accomplished using computational homogenization. The overall aim of this research is to enable multiscale mechanical modeling of hierarchical connective tissues, by developing a software framework and systematically investigating the influence of physical characteristics and assumptions on the predictions from the algorithms. As part of the research, we will develop finite element (FE) based algorithmic and software framework for analysis of nonlinear, multiscale models in biomechanics, based on the open-source FEBio software. To validate these approaches to multiscale modeling, we will construct idealized, multiscale physical surrogates with well-defined nano- and microstructure and perform simultaneous material characterization at the macro- and microscale. This information will be used to develop and validate parametric, multiscale FE models of the physical surrogates. The proposed research will create a significant impact by providing verified, publicly available computational tools, model development and validation methodologies for multiscale mechanics of hierarchical tissues. We anticipate that the results of this research and the software framework will be utilized across a broad range of applications in biology, medicine and beyond. Many heritable diseases directly affect collagen structure and fibrillogenesis, causing relatively well-characterized alterations in structure/organization of type I collagen at multiple levels. The proposed research is fundamentally necessary to enable multiscale mechanical modeling of connective tissues from the nanoscale to the mesoscale. PUBLIC HEALTH RELEVANCE: The proposed research is fundamentally necessary to enable multiscale mechanical modeling of connective tissues from the nanoscale to the mesoscale. An improved understanding of the hierarchical structure and mechanical function of collagen in connective tissues will provide insight into the many disease and injury states that affect collagen structure.